Tumor suppressor genes in human thyroid neoplasms: p53 mutations are associated undifferentiated thyroid cancers

Fagin, James A.

doi:10.1007/bf03349723

Cited by 34 publications

(25 citation statements)

References 11 publications

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“…Total RNA was isolated using RNAgents (Promega Corp., Madison, Wisconsin, USA), according to the manufacturer's recommendation. One microgram of total RNA was treated with DNA-free (Ambion Inc., Austin, Texas, USA) and was reverse-transcribed to cDNA using the Omniscript Reverse Transcriptase kit (QIAGEN Inc., Germantown, Maryland, USA) with oligo-dT [12][13][14][15][16][17][18] primer and 10 U of RNase inhibitor (Invitrogen Corp.). Reverse transcriptase-negative samples were prepared for each individual reaction and were used as controls for detection of assay contamination.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, several molecular markers have been analyzed for their ability to discriminate between benign and malignant follicular tumors, including TPO, TP53, telomerase, and HMBE-1. Nonetheless, these candidate markers have not proved to be of practical value for preoperative FNA diagnosis of FTC (13)(14)(15). More recently, cDNA array technology has been used to identify potentially important thyroid cancer-associated genes (16).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression

Cerutti¹,

Delcelo²,

Amadei³

et al. 2004

J. Clin. Invest.

167

120

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression

Cerutti¹,

Delcelo²,

Amadei³

et al. 2004

J. Clin. Invest.

167

120

View full text Add to dashboard Cite

show abstract

“…19 Moreover, in clinical studies of cancer patients, mutations in p53 frequently correlate with undifferentiated phenotypes of cancers. 35,36 The M1 murine myeloblastic cell line, which is p53-null, can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation. 37 We found that a derivative of this line, the M1/2 cell line, 38 retains the capacity to differentiate in response to IL-6.…”

Section: Introductionmentioning

confidence: 99%

p53 is a regulator of macrophage differentiation

et al. 2004

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While it is well accepted that p53 plays a role in apoptosis, less is known as to its involvement in cell differentiation. Here we show that wild-type p53 facilitates IL-6-dependent macrophage differentiation. Treatment of M1/2 cells expressing the temperature-sensitive p53 143 (Val to Ala) mutant, at the wild-type conformation, facilitated the appearance of mature macrophages that exhibited phagocytic activity. Enhancement of differentiation by the p53 143 (Val to Ala) in the wild-type conformation was coupled with the inhibition of apoptosis induction by this protein. In agreement with previous studies, we found that p53 levels were reduced during p53-dependent macrophage differentiation. This occurred when p53 levels before IL-6 stimuli were high. Interestingly, the p53 143 (Val to Ala) protein, at the mutant conformation, enhanced macrophage differentiation, as did the wild-type conformation, whereas the p53 273 (Arg to His) core mutant exerted an inhibitory effect on this pathway. The transcription-deficient p53 molecules, p53 (22-23) and p53 22,23,143, could not induce p53-dependent differentiation. Moreover, the p53 (22-23) protein inhibited the p53-independent differentiation pathway. Interestingly, the p53 (22-23) protein not only blocked IL-6-mediated differentiation, but also induced significant apoptotic cell death, upon IL-6 stimulation. Taken together, our data show that wild-type p53 enhances macrophage differentiation, while various p53 mutant types exert different effects on this differentiation pathway.

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“…7,8 As one example, mutations of p53 are commonly noted in anaplastic thyroid carcinomas, but they are rarely present in well-differentiated thyroid carcinomas. [9][10][11][12] BRAF encodes a serine-threonine kinase that acts in the mitogen activated protein kinase (MAPK) pathway. 13 Activating BRAF mutations induce constitutive activation of the signal transduction pathway, providing a potent promitogenic force that drives malignant transformation.…”

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confidence: 99%

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

et al. 2004

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Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T)-adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector s assay). Seven of these anaplastic thyroid carcinomas arose in association with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T-A mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing welldifferentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic thyroid carcinoma.

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Tumor suppressor genes in human thyroid neoplasms: p53 mutations are associated undifferentiated thyroid cancers

Cited by 34 publications

References 11 publications

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression

p53 is a regulator of macrophage differentiation

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

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